Cooperative Cu/azodiformate system-catalyzed allylic C–H amination of unactivated internal alkenes directed by aminoquinoline

Aliphatic allylic amines are common in natural products and pharmaceuticals. The oxidative intermolecular amination of C(sp3)-H bonds represents one of the most straightforward strategies to construct these motifs. However, the utilization of widely internal alkenes with amines in this transformation remains a synthetic challenge due to the inefficient coordination of metals to internal alkenes and excessive coordination with aliphatic and aromatic amines, resulting in decreasing the reactivity of the catalyst. Here, we present a regioselective Cu-catalyzed oxidative allylic C(sp3)-H amination of internal olefins with azodiformates to these problems. A removable bidentate directing group is used to control the regiochemistry and stabilize the π-allyl-metal intermediate. Noteworthy is the dual role of azodiformates as both a nitrogen source and an electrophilic oxidant for the allylic C-H activation. This protocol features simple conditions, remarkable scope and functional group tolerance as evidenced by >40 examples and exhibits high regioselectivity and excellent E/Z selectivity.


Reviewer #2 (Remarks to the Author):
The author presented a regioselective Cu-catalyzed oxidative allylic C(sp3)-H amination of internal olefins with azodiformates in the manuscript, achieving good regioselectivity through the use of a bidentate directing group.However, the mechanistic calculations are too crude to elucidate the proton transfer at the amide position in their computational model, provide an unclear explanation for the role of the substrate, and lack discussions on the key factors influencing regioselectivity.Without these details would hinder chemists for further comprehending and expanding upon the reaction.Therefore, I am not unable to consider publish the manuscript.Major: 1.The role of substrate 2a in the reaction mechanism is indeed crucial.Based on the author's computational model, when substrate 1a coordinates with Cu, the N-H bond at the amide position is cleaved.Since no base is introduced into the reaction system, is it plausible to consider that substrate 2a may act as a base, facilitating deprotonation in this step?However, in the mechanism illustrated in Figure 5, substrate 2a appears to exhibit redox properties when it abstracts a hydrogen atom from substrate 1a, causing an increasing oxidation state of Cu.This implies a different functional role for substrate 2a in this particular step.It's essential to provide a more detailed explanation that can clarify why substrate 2a performs different functions in these distinct stages of the reaction.2.In Figure 5, authors propose a transition from Cu(I) to Cu(III) in the mechanism.This is somewhat assertive, and whether there is experimental evidence to confirm the existence of Cu(III) species in the system.
3.The mechanism depicted in Figure 5 is the crucial step determining regioselectivity.The author should provide a detailed analysis based on the transition state structures, examining the nature of hydrogen which is transferred and highlighting the key interactions.Such information would be beneficial for chemists understanding this reaction.4.In Figure 4, the author determined the kinetic isotope effect (KIE) values in experiment for this reaction.To further validate the correctness of the mechanism, the author can also calculate the theoretical KIE values and compare it with the experimental results.Minor： 1.In Table 2, the author uses a red * to mark the active sites.It is possible that the active site for structure 37 is labeled incorrectly.
2.In Figure 3b, the description mentions using ethyl acetate (EA) as the solvent for the reaction in the upper right corner.However, there is a discrepancy in the text, where it states that methanol (MeOH) is the solvent at line 162 3.In Figure 4d, in the deuterium-labeled experiment, based on the mechanism described in the text, the N-H in the structure 58-d2 should be N-D.

Reviewer #3 (Remarks to the Author):
The manuscript entitled "Cooperative Cu/Azodiformate System-Catalyzed Allylic C−H Amination of Unactivated Internal Alkenes" reports a new reaction system for the regio-and stereoselective allylic C-H amination with the azo dicarboxylates.The reaction mechanism is very unique, and the azo dicarboxylate worked as initially electrophile and finally nucleophile.In particular, the C-H cleavage process including Cu, allylic substrate, and azo dicarboxylate deserves significant attention.However, this reviewer has several critical concerns.First, the authors state that this is the allylic C-H amination of "unactivated" internal alkenes, but the substrate is truly "unactivated"?The substrate with the aminoquinoline (AQ) directing group is an apparently "activated" alkene.Of course, this is the first successful application of AQ in the regioselective allylic C-H amination, but the novelty cannot meet the standard level of Nat.Commun.because of here are many precedents of the regio-and stereochemical functionalizations of AQ-containing alkene substrates.At least, the catalytic asymmetric version should be developed.On the basis of the above considerations, I do think that this submission is the borderline case.If the authors are willing to address the aforementioned critical problems, I can support acceptance of this paper.
Additional comments: 1) In the TOC graphic, the word "dehydrogenation" should be replaced with "C-H cleavage".2) Page 2, final line; "direct oxidation of allyl…" should be replaced with "oxidative allylic…".3) In Figure 2c, "Region-selective" should be replaced with "Regio-selective".Additionally, the molecular orientation of starting substrate and product should be consistent with the illustrations.4) In Table 1, is the reaction generally performed under N2 or air?The atmospheric conditions should also be shown in the caption.5) Page 5, final part seems to be unfair, at least, for me.The authors mentioned the traditional Cu-catalyzed allylic substitutions of allyl (pseudo)halides with organometallic reagents, which are totally different and have nothing to do with the present reaction.6) In Table 2, compound 15; the dr value should be shown.7) In Figure 3, compound 48; the dr value should be shown.8) Page 9; there are the grammatical errors in the first sentence.

List of responses 1. Responses to reviewer 1:
1) Comment #1: "The &gt; 10:1 dr for substrates 14 and 15 should be indicated in Table 2." Our Response: Thanks for your suggestions.For substrate 14, due to the presence of only one chiral center in the product, there is no diastereoselectivity.As for substrate 15, the Dr value has been annotated in Table 2.
2) Comment #2: "Is this reaction limited to only diazocarboxylates?The outcome in the case of azobisisobutyronitrile (AIBN) can be included."Our Response: Thanks for your suggestions.Upon screening a wide range of diazo compounds, it was observed that this reaction is limited to diazocarboxylates, with no reactivity observed for other diazo compounds, including AIBN (azobisisobutyronitrile).Given the limitations of the substrate table, we will not include the example of AIBN in Table 2.
3) Comment #3: "In Table 1(entries 1, 3, 4, and 6): these reactions did not furnish the desired product.Is the starting material recovered here?Any side product, if detected, can be specified for a comprehensive understanding."Our Response: Thanks for your suggestions.In Table 1 (entries 1, 2, 3, 4, and 6), the employed metal catalysts exhibited almost no reactivity, resulting in a significant excess of starting material 1a, without any observed generation of other by-products.Furthermore, the starting material is recoverable under these conditions.4) Comment #4: "Compounds 25, 28, 33, 37 are not very pure.Clean NMR spectra may be provided; Compounds 35: 19 F NMR is missing; Compounds 44: the carbonyl signal of estrone is missing in spectra; The melting point of solid new compounds can be reported."Our Response: Thanks for your suggestions.We have carried out a secondary purification of compounds 25, 28, 33, and 37; The 19 F NMR of compound 35 has been completed, as well as the carbonyl signal of estrone in compound 44; The melting points of solid products in the reaction were measured, and all these modifications have been annotated in the supporting information.

Responses to reviewer 2:
1) Comment #1: "The role of substrate 2a in the reaction mechanism is indeed crucial.Based on the author&#039;s computational model, when substrate 1a coordinates with Cu, the N-H bond at the amide position is cleaved.Since no base is introduced into the reaction system, is it plausible to consider that substrate 2a may act as a base, facilitating deprotonation in this step?However, in the mechanism illustrated in Figure 5, substrate 2a appears to exhibit redox properties when it abstracts a hydrogen atom from substrate 1a, causing an increasing oxidation state of Cu.This implies a different functional role for substrate 2a in this particular step.It&#039;s essential to provide a more detailed explanation that can clarify why substrate 2a performs different functions in these distinct stages of the reaction."Our Response: Thanks for your suggestions.Substrate 2a plays a dual role in the reaction mechanism, functioning both as an oxidizing agent and a nitrogen source.According to the reaction mechanism, upon the coordination of substrate 1a with copper, the N-H bond at the amide position undergoes cleavage.Due to the absence of an introduced base in the reaction system, we postulate that substrate 2a may function as a base.We contend that its involvement in promoting deprotonation during this step is reasonable, as there is literature evidence suggesting that azodiformates can act as bases for hydrogen abstraction ( J. Am.Chem.Soc. 1966Soc. , 88, 2328;;J. Org. Chem. 1967, 32, 727;J. Am. Chem. Soc. 2008, 130, 14048).Based on the hypothesis that substrate 2a serves as a base, along with an excess of 2a, we reintroduced the first deprotonation step in the DFT calculation outlined in Figure 5. Facilitated by copper, substrate 2a efficiently abstracts proton from substrate 1a with an energy barrier of 15.6 kcal/mol.Following the extraction of a hydrogen atom from substrate 1a, substrate 2a assumes the role of an oxidant, resulting in an increased oxidation state of copper.It has been reported in certain literature that diazo compounds can function as oxidants (Tetrahedron Lett.2009, 50, 1493; J. Am.Chem.Soc.2018, 140, 1612).
2) Comment #2: "In Figure 5, authors propose a transition from Cu(I) to Cu(III) in the mechanism.This is somewhat assertive, and whether there is experimental evidence to confirm the existence of Cu(III) species in the system."Our Response: Thanks for your suggestions.Reductive elimination of Cu(III) intermediates is often proposed as a key step in many copper-catalyzed or -mediated C-C or C-heteroatom bond-forming reactions.However, there still lacks concrete evidence on this key step, mainly because Cu(III) complexes are usually too unstable to be isolated and structurally characterized.To validate the proposed transition from Cu(I) to Cu(III) in the mechanism, an electron paramagnetic resonance (EPR) experiment was performed to verify whether there was a Cu(II) species during the reaction process.However, the results showed no visible EPR signals corresponding to Cu(II) species.However, we consider the reaction to be an oxidationreduction type, making it less likely to be catalyzed by a Lewis acid.Therefore, we ultimately propose a transition from Cu(I) to Cu(III) in the mechanism.
3) Comment #3: "The mechanism depicted in Figure 5 is the crucial step determining regioselectivity.The author should provide a detailed analysis based on the transition state structures, examining the nature of hydrogen which is transferred and highlighting the key interactions.Such information would be beneficial for chemists understanding this reaction."Our Response: We thank the reviewer for this comment.We have provided an analysis based on transition state structures in the revised manuscript to clarify the regioselectivity.We contend that, during the hydrogen transfer process, the hydrogen atom itself undergoes no inherent property changes.The coordination of copper with diazocarboxylates enhances the basicity of nitrogen atoms, thereby facilitating deprotonation.4) Comment #4: "In Figure 4, the author determined the kinetic isotope effect (KIE) values in experiment for this reaction.To further validate the correctness of the mechanism, the author can also calculate the theoretical KIE values and compare it with the experimental results."Our Response: Thanks for your suggestions.At the same theory level, we have calculated the reaction in KIE experiment and used freqchk script in Gaussian to analyze the result of deuterated reaction.The theoretical KIE values is 3.34, which is close to the experimental results.5) Comment #5: "In Table 2, the author uses a red * to mark the active sites.It is possible that the active site for structure 37 is labeled incorrectly."Our Response: Thanks for your suggestions.Through a literature survey, it was found that both the 2nd and 3rd positions of indole are susceptible to undergo substitution reactions with diazocarboxylates (eg: Tetrahedron 2005, 61, 2401-2405; ACS Catal.2022, 12, 7511−7516).6) Comment #6: "In Figure 3b, the description mentions using ethyl acetate (EA) as the solvent for the reaction in the upper right corner.However, there is a discrepancy in the text, where it states that methanol (MeOH) is the solvent at line 162; In Figure 4d, in the deuterium-labeled experiment, based on the mechanism described in the text, the N-H in the structure 58-d2 should be N-D."Our Response: Thanks for your suggestions.In the revised manuscript, the notation in Figure 3b indicating the use of ethyl acetate (EA) as the reaction solvent in the upper right corner has been corrected to methanol (MeOH).Additionally, the N-H in compound 58-d2 has been revised to N-D in the deuterium-labeled experiment.

Responses to reviewer 3:
1) Comment #1: "First, the authors state that this is the allylic C-H amination of "unactivated" internal alkenes, but the substrate is truly "unactivated"?
2) Comment #2: "At least, the catalytic asymmetric version should be developed."Our Response: We are well aware that asymmetric catalysis is currently a research hotspot.Our initial concept was to develop a catalytic asymmetric method for constructing chiral C-N bonds, with the aim of elevating the quality of our manuscripts.Following a year of systematic experimental screening, the highest enantioselectivity we achieved was 25%.Consequently, we made the decision to temporarily halt chiral screening, and we sincerely regret this choice.Due to the unsatisfactory results, we have opted against including this segment of the screening work in the manuscript.However, in the following sections, I will present a subset of the screening results for the reviewer's consideration, with the expectation that valuable insights can be provided.
Table 1 In table 1, CuCl was employed as the catalyst for screening various chiral ligands (some other ligands are not listed in the table 1).It was observed that only the (R)-BINAP ligand exhibited a 6% ee value.However, the remaining ligands failed to exert chiral control.
Table 2 In Table 2, (R)-BINAP was selected as the chiral ligand, a screening of copper metal salts catalysts was conducted.The results indicate that CuTc, in comparison to other copper catalysts, achieved an 11% ee value.
Table 3 In Table 3, CuTc was employed as the catalyst for a systematic screening of phosphine ligands.It is evident that the majority of phosphine ligands exhibited enantioselectivity; however, the results were somewhat unsatisfactory.Only the (R,R)-(-)-2,3-Bis(tbutylmethylphosphino)quinoxaline ligand demonstrated a 25% ee value.Table 4 In Table 4, CuTc was selected as the catalyst, and (R,R)-(-)-2,3-Bis(tbutylmethylphosphino)quinoxaline was chosen as the chiral ligand.Solvent screening was conducted, revealing that toluene exhibited comparatively favorable results.
Subsequently, we conducted screenings on substrate ratios, reaction temperatures, and additives, but no breakthroughs were attained.The optimal outcome achieved was a 25% enantiomeric excess.The following exploratory experiments were conducted, and an analysis of the screening results was performed.
Table 5 In Table 5, preformed complexes A and B were prepared.Under standard conditions, substrate 1a was introduced into the system.After several hours, the appearance of ligand E and ligand F on the TLC plate was distinctly observed.This result indicates an excessively strong coordinating ability of AQ, leading to ligand exchange and subsequent dissociation of the chiral ligand, thereby preventing the establishment of a chiral environment.We conducted an analysis of the system.Firstly, we identified the limited coordination ability of copper ions.Additionally, there are numerous substrate moieties available for coordination within the system, including the two nitrogen atoms on AQ in substrate 1a and the two nitrogen atoms in azodiformates.The introduction of a chiral ligand further exacerbates the issue, as there are too many compounds within the system that can coordinate with copper.This leads to a competitive coordination scenario, making it challenging to maintain a chiral reaction environment.
Despite the unsatisfactory outcomes of the catalytic asymmetric version, the introduction of chiral auxiliaries for asymmetric induction is a well-established method in the field of organic synthesis and has been encouraged by the work of Meyer and Yu.Envisaging the potential to achieve diastereoselectivity in allylic C-H amination through the use of a chiral oxazoline amide as a directing group, we conducted a series of screenings.The results are as follows: Table 6 In Table 6, we initially investigated substituents with varying steric hindrance on the oxazoline ring, including methyl, phenyl, isopropyl, tert-butyl, and indanyl groups.Gratifyingly, the phenyl group demonstrated a high diastereoselectivity (>15:1) and a moderate yield.Conversely, the tert-butyl and indanyl groups were found to suppress the reaction due to their substantial steric hindrance effects.Subsequently, we expanded the substrate scope by introducing alkyl chain R groups.In the table, only a few representative substrates are included.The results indicate that none of them exhibited a diastereoselectivity greater than 5:1.This observation suggests that steric hindrance from the R group influences the control of enantioselectivity, leading to incompatibility between the chiral directing group and the R group.
Prior to submission, we made the decision to exclude the section on chiral screening from the manuscript as we did not achieve satisfactory enantioselectivity.Subsequently, an in-depth analysis and exploration were conducted on this aspect of the work.We attribute the difficulty in achieving high ee value to the presence of an AQ-directing group in the substrate.We have also attempted to remove the AQ-directing group and transform it into a chiral ligand for screening in allylic C-H amination reactions.The screening process is still ongoing.Finally, we also hope that the reviewers can provide guidance and suggestions on the aforementioned screening results.
3) Comment #3: "In the TOC graphic, the word "dehydrogenation" should be replaced with "C-H cleavage; Page 2, final line; "direct oxidation of allyl…" should be replaced with "oxidative allylic…; In Figure 2c, "Region-selective" should be replaced with "Regioselective"; Additionally, the molecular orientation of starting substrate and product should be consistent with the illustrations."Our Response: Thanks for your suggestions.We changed "dehydrogenation"(in the TOC graphic) to "C-H cleavage", changed "direct oxidation of allyl…"(in Page 2, final line) to "oxidative allylic…", changed "Region-selective"(in Figure 2c) to "Regio-selective", changed the molecular orientation of starting substrate and consistent with the illustrations.4) Comment #4: "In Table 1, is the reaction generally performed under N2 or air?The atmospheric conditions should also be shown in the caption."Our Response: Thanks for your suggestions.The reaction proceeds successfully under both N2 and air conditions.In Table 1, entry 21, screening under Ar conditions has been conducted.Atmospheric conditions have been indicated in the caption.5) Comment #5: "Page 5, final part seems to be unfair, at least, for me.The authors mentioned the traditional Cu-catalyzed allylic substitutions of allyl (pseudo)halides with organometallic reagents, which are totally different and have nothing to do with the present reaction."Our Response: Thanks for your suggestions.We have discussed this matter and agree with the reviewer's opinion, considering that the relevance is not significant.We have already removed the relevant content in the revised manuscript.
6) Comment #6: "In Table2, compound 15; the dr value should be shown; In Figure3, compound 48; the dr value should be shown; Page 9; there are the grammatical errors in the first sentence."Our Response: Thanks for your suggestions.For compounds 15 and 48, their Dr values have been annotated in the revised manuscript.The grammatical error in the first sentence on page 9 has been corrected in the revised manuscript.